The broad long-term objective of this research is to improve treatment of children with intraocular retinoblastoma by utilizing animal modeling of current and experimental therapies to enhance tumor control while decreasing treatment related morbidity. Extensive pilot data, utilizing a unique transgenic model of intraocular retinoblastoma, has documented the reliability of this approach to model human retinoblastoma and its response to treatment. [unreadable] Retinoblastoma is the most common primary intraocular tumor in children. This cause of this disease is characterized on a molecular genetic level as inactivation of both copies of the retinoblastoma gene. It is now recognized that this genetic defect predisposes children to a lifelong risk of second, independent malignancies. The incidence of these malignancies is affected by the treatment chosen to cure the primary eye tumor. Over the last decade, external beam radiotherapy has virtually been eliminated as an initial treatment option in childhood retinoblastoma and has been replaced by systemically delivered chemotherapy coupled to local tumor treatment with laser ablation or cryoablation. Complications during this treatment are expected to occur in up to two-thirds of treated children. Focally delivered chemotherapy (relatively easily due to the unique accessibility and anatomy of the eye and orbit) reduces complications related to systemic delivery and has been shown to be effective in pilot labora-tory studies and in early pilot treatment projects in children with retinoblastoma. Retinoblastoma is a highly vascularized tumor. Pilot data suggests that angiostatic therapy is effective in the reduction of tumor burden in a murine transgenic model of retinoblastoma. This model system will be used to evaluate the efficacy of focally delivered vascular targeting agents in the treatment of retinal tumors. [unreadable] Dose dependent reduction of tumor burden and blood vessel closure will be determined for two different vascular targeting agents. These individual therapies will be combined with focal/ subconjunctival Carboplatin chemotherapy. The optimal drug concentrations and delivery schedules for the combined treatment will be determined. [unreadable] To understand disease progression and to identify potential novel therapeutic agents, the processes of angiogenesis and tumor cell death during tumor progression and in response to treatment will be assessed. [unreadable] The differential expression and localization of angiogenesis promoting factors will be determined during tumor progression and following treatment; The spontaneous induction of tumor cell death (necrosis or apoptosis) will be determined during tumor progression and the differential induction of tumor cell death will be assessed following each treatment modality. It is likely that results from these studies will contribute immediately to the care of children with this devastating ocular malignancy. [unreadable] [unreadable] [unreadable]